IMMUNO INHIBITORY PYRAZOLONE COMPOUNDS

Description

[0001] The present invention relates to pyrazolone compounds, to methods for their preparation, to compositions containing them, and to methods and use for clinical treatment of medical conditions which may benefit from immunomodulation, e.g. rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis. More particularly the present invention relates to pyrazolone compounds, which are CD80 antagonists capable of inhibiting the interactions between CD80 and CD28.

Background to the Invention

[0002] The immune system possesses the ability to control the homeostasis between the activation and inactivation of lymphocytes through various regulatory mechanisms during and after an immune response. Among these are mechanisms that specifically inhibit and/or turn off an immune response. Thus, when an antigen is presented by MHC molecules to the T-cell receptor, the T-cells become properly activated only in the presence of additional co-stimulatory signals. In the absence of these accessory signals there is no lymphocyte activation and either a state of functional inactivation termed anergy or tolerance is induced, or the T-cell is specifically deleted by apoptosis.

[0003] One such co-stimulatory signal involves interaction of CD80 on specialised antigen-presenting cells with CD28 on T-cells, and this signal has been demonstrated to be essential for full T-cell activation. (Lenschow et al. (1996) Annu. Rev. Immunol., 14, 233-258). It would therefore be desirable to provide compounds which inhibit this CD80/CD28 interaction.

[0004] WO 03/004495 A1 discloses 3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-derivatives as immunomodulating heterocyclic compounds, a pharmaceutical composition comprising said compound, a method and use of said compound for clinical treatment of medical conditions which may benefit from immunododulation. More particularly, this document relates to novel heterocyclic compounds, which are CD80 antagonists capable of inhibiting the interaction between CD80 and CD28. Accordingly, this document does neither mention nor suggest the pyrazolone compounds of the present invention which are CD80 antagonists capable of inhibiting the interactions between CD80 and CD28.

[0005] US 5,061,705 discloses diarylsubstituted five-membered or six-membered heterocyclic compounds, processes for their preparation and their use of the prophylaxis and treatment of disorders. This document neither mentions nor suggests the immunomodulating pyrazolone compounds of the present invention. In addition, this document does not mention immunomodulation at all, and moreover, this document is also completely silent with respect to any inhibition of CD80-CD28 interaction.

[0006] In Farmaco, Edizione Scientifica., vol. 39, no. 4, 1984, 371-378 Picciola G. et al. disclose the synthesis and pharmacological study of some derivatives of 2,4-dihydro-3H-pyrazol-3-one in which the compound [2-(4-carboxymethylphenyl)-4-phenyl-5-methyl-2,4-dihydropyrazol-3-one proved to have antipyretic activity equal to that of ibuprofen and aminopyrine. Accordingly, the document does not mention the specific immunodulating pyrazolones of the present invention.

[0007] Likewise, EP 0269030 A2 which discloses pyrazolone derivatives having inhibitory activity and their pharmaceutically acceptable salts does neither mention nor suggest the CD80 antagonists of the present invention. Moreover, the compounds of this document aim at the inhibition of completely different diseases as is the case for the claimed CD80 antagonists.

[0008] In Journal für Praktische Chemie vol. 2, 121, 1929, p. 201 K. Heller discloses pyrazolone derivatives which, however, differ in their structure from the CD 80 antagonists of the present invention.

[0009] In Tetrahedron Letters 44 (2003), pages 8063-8067 Jang-Woon Byun et al. describe the preparation of solid-phase active esters from a new pyrazolone linker resin and in this context they mention the pyrazolone linker 1-(4-carboxyphenyl)-3-(4-nitrophenyl)-2-pyrazolin-5-one which differs with regard to its structure from the CD80 inhibitors of the present invention.

[0010] Likewise, the urea and thiourea of 1-(4-aminophenyl)-3-phenyl-5-pyrazolone described in GB 629 412 A differ in their structure from the particular compounds of the present invention and moreover, do not have the desired activity as CD80 inhibitors.

[0011] Also the pyrazolone compounds mentioned in US 3,576,637 do not have the desired structure of the claimed compounds of the present invention. In addition, this document discloses a lith-type emulsion which has improved contrast and halftone dot quality. Moreover, since this documents mentions that a pyrazolone compound is incorporated with an alkylene oxide in a silver halide emulsion it relates to a completely different field than the compounds of the present invention.

[0012] Likewise, EP 0255892 A2 which discloses pyrazolone derivatives as special white coupler for use in a recording material which contains, on a light-reflecting base, at least three silver halide emulsion layers, arranged thereon, of different spectral sensitivity and associated colour couplers, a special 2-equivalent yellow coupler and a special white coupler being associated with the blue-sensitive silver halide emulsion layer relates to a completely different field.

[0013] Michaelis in Justus Liebigs Ann. Chem.; 373; 1910; 167 and the Japanese patent application JP45-26736 each disclose specific pyrazolone derivatives which, however, differ in their structure from the claimed CD80 inhibitors of the present invention.

Detailed Description of the Invention

[0014] The present invention contemplates a compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof:

wherein
Ar represents an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group having from 5 to 10 ring atoms,
R₁ and R₂ independently represent H, or C₁-C₆ alkyl;
R₃ represents H; F; Cl; Br; -NO₂; -CN; C₁-C₆ alkyl optionally substituted by F or Cl; or C₁-C₆ alkoxy optionally substituted by F;
R₄ represents a carboxylic acid group (-COOH) or an ester thereof, or -C(=O)NR₆R₇, -NR₇C(=O)R_6, -NR₇C(=O)OR₆, -NHC(=O)NR₇R₆ or-NHC(=S)NR₇R₆ wherein
R₆ represents H, or a radical of formula -(Alk)_m-Q wherein
m is 0 or 1
Alk is an optionally substituted divalent straight or branched C_1-C₁₂ alkylene, or C_2-C₁₂ alkenylene, or C_2-C₁₂ alkynylene radical or a divalent C_3-C₁₂ carbocyclic radical, any of which radicals may be interrupted by one or more -O-, -S- or -N(R₈)- radicals wherein R₈ represents H or C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, or C₃-C₆ cycloalkyl, and
Q represents H; -CF₃; -OH; -SH; -NR₈R₈ wherein each R₈ may be the same or different, or form a ring when taken together with the nitrogen to which they are attached; an ester group; or an optionally substituted aryl, aryloxy, cycloalkyl, cycloalkenyl or heterocyclic group; and
R₇ represents H or C₁-C₆ alkyl; or when taken together with the atom or atoms to which they are attached R₆ and R₇ form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms; and
X represents a bond or a divalent radical of formula -(Z)_n-(Alk)- or -(Alk)-(Z)_n- wherein Z represents -O-, -S- or -NH-, Alk is as defined in relation to R₆ and n is 0 or 1.

[0015] Compounds (IA) may exist in the form of tautomers (IA¹):

[0016] Hereafter, the compounds (IA) of the invention may be represented and referred to in either tautomeric form and it is to be understood that any and all tautomeric forms of structures (IA) and (IB), in particular (IA), may be included in the invention.

[0017] Compounds of general formula (IA) and (IB) are CD80 antagonists. They inhibit the interaction between CD80 and CD28 and thus the activation of T cells, thereby modulating the immune response.

[0018] Accordingly the invention also contemplates :

(i) a compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt thereof for use in the treatment of conditions which benefit from immunomodulation.

(ii) the use of a compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which benefit from immunomodulation,.

(iii) a method of immunomodulation in mammals, including humans, comprising administration to a mammal in need of such treatment an immunomodulatory effective dose of a compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt thereof.

(iv) a pharmaceutical or veterinary composition comprising a compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt thereof together with a pharmaceutically or veterinarily acceptable excipient or carrier.

[0019] Conditions which benefit from immunomodulation include:

Acute disseminated encephalomyelitis

Adrenal insufficiency

Allergic angiitis and granulomatosis

Amylodosis

Ankylosing spondylitis

Asthma

Autoimmune Addison's disease

Autoimmune alopecia

Autoimmune chronic active hepatitis

Autoimmune haemolytic anaemia

Autoimmune Neutrogena

Autoimmune thrombocytopenic purpura

Behçet's disease

Cerebellar degeneration

Chronic active hepatitis

Chronic inflammatory demyelinating polyradiculoneuropathy

Chronic neuropathy with monoclonal gammopathy

Classic polyarteritis nodosa

Congenital adrenal hyperplasia

Cryopathies

Dermatitis herpetiformis

Diabetes

Eaton-Lambert myasthenic syndrome

Encephalomyelitis

Epidermolysis bullosa acquisita

Erythema nodosa

Gluten-sensitive enteropathy

Goodpasture's syndrome

Guillain-Barre syndrome

Hashimoto's thyroiditis

Hyperthyroidism

Idiopathic hemachromatosis

Idiopathic membranous glomerulonephritis

Isolated vasculitis of the central nervous system

Kawasaki's disease

Minimal change renal disease

Miscellaneous vasculitides

Mixed connective tissue disease

Multifocal motor neuropathy with conduction block

Multiple sclerosis

Myasthenia gravis

Opsoclonus-myoclonus syndrome

Pemphigoid

Pemphigus

pernicious anaemia

Polymyositis/dermatomyositis

Post-infective arthritides

Primary biliary sclerosis

Psoriasis

Reactive arthritides

Reiter's disease

Retinopathy

Rheumatoid arthritis

Sclerosing cholangitis

Sjögren's syndrome

Stiff-man syndrome

Subacute thyroiditis

Systemic lupus erythematosis

Systemic necrotizing vasculitides

Systemic sclerosis (scleroderma)

Takayasu's arteritis

Temporal arteritis

Thromboangiitis obliterans

Type I and type II autoimmune polyglandular syndrome

Ulcerative colitis

Uveitis

Wegener's granulomatosis

[0020] As used herein, the term "ester" refers to a group of the form -COOR, wherein R is a radical notionally derived from the alcohol ROH. Examples of ester groups include the physiologically hydrolysable esters such as the methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, and benzyl esters.

[0021] As used herein the term "alkylene" refers to a straight or branched alkyl chain having two unsatisfied valencies, for example -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH(CH₃)CH₂-, -CH(CH₂CH₃)CH₂CH₂CH₂-, and -C(CH₃)₃.

[0022] As used herein the term "alkenylene" refers to a straight or branched alkenyl chain having two unsatisfied valencies, for example-CH=CH-, -CH₂CH=CH-, -C(CH₃)=CH-, and -CH(CH₂CH₃)CH=CHCH₂-.

[0023] As used herein the term "alkynylene" refers to a straight or branched alkynyl chain having two unsatisfied valencies, for example-C≡C-, -CH₂C≡C-, and -CH(CH₂CH₃)C≡CCH₂-.

[0024] Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with at least one substituent, for example selected from (C₁-C₆)alkyl, trifluoromethyl, (C₁-C₆)alkoxy (including the special case where a ring is substituted on adjacent ring C atoms by alkylenedioxy such as methylenedioxy or ethylenedioxy), trifluoromethoxy, (C₁-C₆)alkylthio, phenyl, benzyl, phenoxy, benzyloxy, hydroxy, mercapto, amino, fluoro, chloro, bromo, cyano, nitro, oxo, -COOH, -SO₂OH, -CONH₂, -SO₂NH₂, -COR^A, -COOR^A, -SO₂OR^A, -NHCOR^A, -NHSO₂R^A, -CONHR^A, -SO₂NHR^A, -NHR^A, -NR^AR^B, -CONR^AR^B or -SO₂NR^AR^B wherein R^A and R^B are independently a (C₁-C₆)alkyl or C₂ - C₆ alkoxy group or a monocyclic carbocyclic or heterocyclic group of from 5-7 ring members, or R^A and R^B form a ring when taken together with the nitrogen to which they are attached. In the case where "substituted" means substituted by phenyl, benzyl, phenoxy, or benzyloxy, the phenyl ring thereof may itself be substituted with any of the foregoing, except phenyl, benzyl, phenoxy, or benzyloxy.

[0025] As used herein the term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical, and to two such radicals covalently linked to each other, Illustrative of such radicals are phenyl, biphenyl and napthyl.

[0026] As used herein the unqualified term "carbocyclyl" or "carbocyclic" includes aryl, cycloalkyl and cycloalkenyl and refers to a ring system (monocyclic, bicyclic, tricyclic or bridged) whose ring atoms are all carbon.

[0027] As used herein the unqualified term "cycloalkyl" refers to a carbocyclic ring system which contains only single bonds between ring carbons.

[0028] As used herein the unqualified term "cycloalkenyl" refers to a carbocyclic ring system which contains at least one double bond between a pair of ring carbons.

[0029] As used herein the term "heteroaryl" refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.

[0030] As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and in particular means a mono-, bi- or tri-cyclic or bridged non-aromatic radical containing one or more heteroatoms selected from S, N and O and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.

[0031] Some compounds of the invention contain one or more chiral centres because of the presence of asymmetric carbon atoms. The presence of asymmetric carbon atoms gives rise to stereoisomers or diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such stereoisomers and diastereoisomers and mixtures thereof.

[0032] Salts of salt forming compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates; and base addition salts, for example sodium, potassium, magnesium, and calcium salts.

Methods

[0033] Compounds of formula (IA) described herein wherein R₁ is hydrogen and wherein R₄ represents an amide group
-C(=O)NR₆R₇ may be prepared by reaction of the appropriate amine HNR₆R₇ with a compound of formula (II) to amidate the carboxylic acid group:

the symbols Ar, R₃, X, R₆ and R₇ being as defined in relation to formula (I) above.

[0034] Compounds (II) (ie compounds (IA) described herein wherein R₁ is hydrogen and R₄ is a carboxylic acid group) may be prepared by reaction of a compound of formula (III) with a hydrazine of formula (IV):

[0035] This reaction may result in the preparation of a mixture of the position isomers (IIA) and (IIB):

from which the desired isomer (IIA) may be separated.

[0036] Compounds (IA) wherein R₁ is hydrogen and R₄ is an amide (-C(=O)NR₆R₇) or ester group may also be prepared from intermediate (III) by reaction with the appropriate hydrazine (IVA)

wherein R₄ is the amide or ester group. Again the reaction may result in a mixture of the ester analogues of the carboxylic acids (IIA) and (IIB), from which the desired ester isomer (I) may be separated. Alternatively, the carboxylic acid compound (II) may simply be esterified, or amidated (the latter being a route referred to above).

[0037] Compounds (IA) wherein R₁ is hydrogen and R₄ is a "reverse amide" group - NR₇C(=O)R₆ may be prepared by Curtius rearrangement (see Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron (1974), 30(14), 2151-7) of the carboxylic acid (II) to the isocyanate (V)

followed by hydrolysis of the isocyanate group to an amino group and acylation of the amino group with, for example, the acid chloride Cl-C(=O)R₆. In cases where R₇ is not hydrogen, the R₇ substituent may be introduced after the isocyanate reduction step or after the acylation step.

[0038] Compounds (IA) wherein R₁ is hydrogen and R₄ is a urea group - NHC(=O)NHR₆ or thiourea group -NHC(=S)NHR₆ may also be prepared from the isocyanate (V) or the corresponding isothiocyanate by reaction with the appropriate amine H₂NR₆.

[0039] Compounds (I) wherein R₄ is a carbamate group -NR₇C(=O)OR₆ may be prepared by the reaction of the isocyanate with an appropriate alcohol R₆OH.

[0040] Compounds (IA) and (IB) wherein R₁ and R₂ are C₁-C₆ alkyl may be prepared by alkylation of the corresponding compound (IA) wherein R₁ is hydrogen.

[0041] Further details of the synthetic methods for the preparation of compounds (I) as herein described , and intermediates such as (III), may be found in the examples herein.

[0042] In the compounds herein described:

R₁ and R₂ independently represent hydrogen or C₁-C₆ alkyl, such as methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl.

R₄ represents a carboxylic acid group (-COOH) or an ester thereof, or -C(=O)NR₆R₇, -NR₇C(=O)R₆, -NR₇C(=O)OR₆ or -NHC(=O)NHR₆, all as defined above.
When R₄ is an ester group, examples include those of formula -COOR wherein R is methyl, ethyl n- or iso-propyl, n-, sec- or tert-butyl, or benzyl ester.
R₆, when present, represents H, or a radical of formula -(Alk)_m-Q wherein m, Alk and Q being as defined above. When m is 1, Alk may be, for example a straight or branched C₁-C₆ alkylene radical, such as -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, and -CH₂CH(CH₃)CH₂-. Alk may also be, for example, a divalent cyclopropylene, cyclopentylene or cyclohexylene radical. The radical Alk may be optionally substituted by, for example, OH, oxo, CF₃, methoxy or ethoxy. The radical Alk may optionally contain a hetero atom, for example in the form of an ether, thioether or amino linkage.
The group Q may represent, for example, hydrogen; -NR₈R₈ wherein each R₈ may be the same or different and selected from hydrogen, methyl, ethyl, n- or isopropyl or tert-butyl; an ester group for example a methyl, ethyl or benzyl ester, or an optionally substituted aryl, aryloxy, cycloalkyl, cycloalkenyl or heterocyclic group, for example phenyl, phenoxy, cyclopentyl, cyclohexyl, furyl, thienyl, piperidyl, or piperazinyl group.
R₇ when present represents H or C₁-C₆ alkyl, for example methyl, ethyl n- or iso-propyl, n-, sec- or tert-butyl; or when taken together with the atom or atoms to which they are attached R₆ and R₇ form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms;

[0043] Ar may be, for example, optionally substituted phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-furyl, 2-, or 3-thienyl, benzfur-2-yl, or benzthien-2-yl. Optional substituents in Ar include, for example F, Cl, methyl, methoxy, or methylenedioxy. Currently it is suitable that Ar is 3-fluorophenyl and 2-, or 3-furyl,

[0044] R₃ may be, for example, H, F, Cl, methyl, methoxy, or methylenedioxy. Currently R₃ being is very suitable.

[0045] X may be, for example a bond, or a -CH₂- or -CH₂CH₂- radical. A bond is presently suitable.

[0046] According to the present invention there is provided a compound of formula (IC) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof:

wherein
Ar represents an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group having from 5 to 10 ring atoms,
R₆ represents a radical of formula -Alk-Q wherein
Alk is an optionally substituted divalent straight or branched C₁-C₁₂ alkylene, or C₂-C₁₂ alkenylene, or C₂-C_l2 alkynylene radical or a divalent C₃-C₁₂ carbocyclic radical, any of which radicals may be interrupted by one or more -O-, -S- or -N(R₈)- radicals wherein R₈ represents H or C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, or C₃-C₆ cycloalkyl, and
Q represents -NR₈R₈ wherein each R₈ may be the same or different, or form a ring when taken together with the nitrogen to which they are attached; and
R₇ represents H or C₁-C₆ alkyl; or when taken together with the atom or atoms to which they are attached R₆ and R₇ form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms.

[0047] In one embodiment of the invention there is provided a compound of the invention wherein Alk is -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, or -CH₂CH(CH₃)CH₂-, or a divalent cyclopropylene, cyclopentylene or cyclohexylene radical, optionally substituted by OH, oxo, CF₃, methoxy or ethoxy, and Q represents -NR₈R₈ wherein each R₈ may be the same or different and selected from hydrogen, methyl, ethyl, n- or isopropyl or tert-butyl.

[0048] Preferred is a compound of the invention wherein R₇ represents hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl; or when taken together with the atom or atoms to which they are attached R₆ and R₇ form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms.

[0049] A further embodiment of the invention is a compound wherein Ar is optionally substituted phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-furyl, 2-, or 3-thienyl, benzfur-2-yl, or benzthien-2-yl.

[0050] Another embodiment of the invention is a compound of the invention wherein Ar is substituted by F, Cl, methyl, methoxy, or methylenedioxy.

[0051] Further preferred is a compound of the invention wherein Ar is 3-fluorophenyl, or 2- or 3-furyl.

[0052] Specific compounds of the invention are mentioned in the Examples herein.

[0053] As mentioned above, the invention contemplates pharmaceutical or veterinary composition comprising a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof together with a pharmaceutically or veterinarily acceptable excipient or carrier. In such compositions, it will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the cause and severity of the particular disease undergoing therapy. Optimum dose levels and frequency of dosing will be determined by clinical trial.

[0054] The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

[0055] For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.

[0056] For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.

[0057] The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.

[0058] Accordingly, another embodiment of the invention is a pharmaceutical or veterinary composition comprising a compound of the invention together with a pharmaceutically or veterinarily acceptable excipient or carrier.

[0059] Embodiments of the invention are described in the following non-limiting Examples:

[0060] The following abbreviations are used in the experimental descriptions:

DMF

Dimethyl formamide

DMA

Dimethyl acetamide

DMSO

Dimethyl sulphoxide

THF

Tetrahydrofuran

HBTU

O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate

HPLC

High performance liquid chromatography

LCMS

Liquid chromatography mass spectrum

NMR

Nuclear magnetic resonance spectroscopy

Example 1

4-(5-Oxo-3-pyrazin-2-yl-2,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0061] 

Step 1: Preparation of 4-(N'-tert-Butoxycarbonyl-hydrazino)-benzoic acid

[0062] 

[0063] To a deep red solution of p-hydrazinobenzoic acid (32.86 mmol, 5.00 g) in 2M NaOH (100 ml) and THF (70 ml) was added di-tertbutyl dicarbonate (2.0 eq, 65.72 mmol, 14.34 g). This was stirred at rt over a weekend. Another aliquot of di-tertbutyl dicarbonate (3.5 g) was added to the reaction mixture, and this stirred at room temp for a further 24 hours. A further 0.5 eq p-hydrazinobenzoic acid added to the reaction mixture. This was then stirred for a further 24 hours. 10% citric acid solution was added until a pH of 4 was obtained. The product was then extracted with ethyl acetate, the organics washed with brine, and then dried over Na₂SO₄. Concentration in vacuo afforded a pale yellow oil, containing residual tert-BuOH. Hexane was added to the mixture. Precipitation was observed and the solids were collected by filtration, washed with hexane and dried under vacuum at 35°C. An orange powder was obtained (8.40 g).

Step 2: Preparation of N'-[4-(1,2,2,6,6-Pentamethyl-piperidin-4-ylcarbamoyl)-phenyl]-hydrazinecarboxylic acid tert-butyl ester

[0064] 

[0065] To a solution of 4-(N'-tert-Butoxycarbonyl-hydrazino)-benzoic acid (4.452g) in DMA (30ml) was added disopropyl ethyl amine (6.16ml) and HBTU (6.69g) with stirring at room temp. 4-Amino-1,2,2,6,6-pentamethylpiperidine (3g) was then added to the stirred solution. Stirring continued at room temp for 4hrs. The solution was partitioned between ethyl acetate (6 X 20 ml) and water. The organic fraction was taken, washed with brine, dried over MgSO₄ and the solvent removed under vacuum. This revealed a deep orange oil (6.2g, 86%).

Step 3: Preparation of 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0066] 

[0067] N'-[4-(1,2,2,6,6-Pentamethyl-piperidin-4-ylcarbamoyl)-phenyl]-hydrazinecarboxylic acid tert-butyl ester was dissolved in 4M HCl in dioxane (30ml) and left to stir for 1-2hrs. The solution went quickly from a deep orange colour to a bright orange colour. After 1 hr reaction time, the solvent was removed under vacuum to reveal an orange oil that under a vacuum for several minutes crystalised out to give orange crystals in a sticky orange oil. Yield: 4.68 g, 87%.

Step 4: Preparation of 3-Oxo-3-pyrazin-2-yl-propionic acid, ethyl ester.

[0068] 

[0069] To a stirred solution of diethyl malonate (1.25 ml, 1.32g) in THF (20 ml) under an atmosphere of nitrogen at -60°C was added nbutyl lithium (2.5 M, 9 ml) dropwise over 15 min, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 min, the reaction was cooled to -78°C, when a solution of pyrazine-2-carbonyl chloride (0.5 g, dark purple solution in THF (10 ml)) was added dropwise over 15 min. The reaction then warmed to -45°C and stirred for 1 h. The reaction was then poured into 1 M HCl solution (35 ml) with stirring. This was transferred to a separating funnel, and extracted with CH₂Cl₂ (2 x 150 ml). The combined organic layers were then washed with sat. NaCO₃ soln (1 x 30 ml) and then dried over MgSO₄, filtered and concentrated in vacuo to give the product as a brown oil. Yield 0.65g, 45%.

Step 5: Preparation of 4-(5-Oxo-3-pyrazin-2-yl-2,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0070] 

[0071] 3-Oxo-3-pyrazin-2-yl-propionic acid, ethyl ester (78 mg) and 4-hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (141mg) were dissolved in ethanol (3.5 ml) and acetic acid (0.5 ml) and the solution stirred at 65 °C for 2h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 434)

Example 2

4-(3-Isoxazol-5-yl-5-oxo-2,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0072] 

Step 1: Preparation of 3-lsoxazol-5-yl-3-oxo-propionic acid ethyl ester

[0073] 

[0074] To a stirred solution of diethyl malonate (2.6 ml, 2.74g) in THF (40 ml) under an atmosphere of nitrogen at -60°C was added nbutyl lithium (2.5 M, 18.9 ml) dropwise over 15 mins, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 mins, the reaction was cooled to -78°C, when a solution of Isoxazole-5-carbonyl chloride (1 g) in THF (10 ml) was added dropwise over 15 mins. The reaction then warmed to -45°C and stirred for 1 h, the solution had gone pale brown. The reaction was then poured into 1 M HCl solution (50 ml) with stirring and extracted with CH₂Cl₂ (2 x 150 ml). The combined organic layers were washed with sat. NaCO₃ soln (1 x 30 ml), dried over MgSO₄, filtered and concentrated in vacuo to give the product as a pale oil which was used as such in the next step. Yield 1.1g, 35.1%.

Step 2: Preparation of 4-(3-Isoxazol-5-yl-5-oxo-2,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0075] 

[0076] 3-lsoxazol-5-yl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (93 mg) were dissolved into ethanol (2.5 ml) and acetic acid (0.3 ml) and the solution stirred at 65 °C for 2h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 424.3)

[0077] The compound of Example 2 had activity rating * in the HTRF assay described below.

Example 3

4-(3-Furan-2-yl-4-methyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0078] 

Step 1: Preparation of 3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester

[0079] 

[0080] In a flask were placed ethyl 3-(2-furyl)-3-oxopropanoate (0.5g), iodomethane (0.14 ml), finely ground potassium carbonate (0.75g) and acetone (5 ml). The mixture was stirred at reflux for 2h. A further portion of iodomethane (0.9mmol, 0.056 ml) and potassium carbonate (0.9 mmol, 0.12g) were added and the mixture stirred at reflux for 1 h. The reaction mixture was filtered and concentrated under vacuum. Yield (0.5g, 93%).

Preparation of 4-(3-Furan-2-yl-4-methyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0081] 

[0082] 3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (85 mg) in 0.5 ml of acetic acid were heated up at 65 °C for 2h. Concentration in vacuo and purification by HPLC gave the expected product. MH+ = 437.3

[0083] The compound of Example 3 had activity rating * in the HTRF assay described below.

Example 4

4-(3-Furan-2-yl-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0084] 

Step 1: Preparation of 3-Furan-2-yl-2,2-dimethyl-3-oxo-propionic acid ethyl ester

[0085] 

[0086] 3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester (49 mg) was added sodium ethoxide (0.22 ml) and 0.5 ml ethanol. A solid precipitates. The solution was stirred at room temperature for 1h, iodomethane was added and the suspension stirred at room temperature for 3 h. Concentration in vacuo and purification by HPLC gave the expected product.

Step 2: Preparation of 4-(3-Furan-2-yl-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide

[0087] 

[0088] 3-Furan-2-yl-2,2-dimethyl-3-oxo-propionic acid ethyl ester (53 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (85 mg) in 0.5 ml of acetic acid were heated up at 65 °C for 2h. Concentration in vacuo and purification by HPLC gave the expected product (MH+: 451.4)

Additional Examples

[0089] Further examples of compounds of the invention were synthesised by methods analogous to those of Examples 1 - 2 above. The structures of the synthesised compounds are shown in the following Table, together with their activity ratings in the HTRF assay described below.

Table 1

Example	Z	W	R	MH+	Activity Rating
5	Ph	H	CH2CH2CH2N(Me)2	365.2	**
6	Ph	H		482.1	*
7	Ph	H		433.5	**
8	Ph	H		405.5	***
9	Ph	H		419.5	**
10	2-Pyridyl	H	CH2CH2CH2N(Me)2	366.5	***
11	2-furyl	H	CH2CH2CH2N(Me)2	355.4	***
12	3-Pyridyl	H	CH2CH2CH2N(Me)2	366.5	**
13	2-Pyridyl	H		420.5	**
14	2-furyl	H		409.5	***
15	3-Pyridyl	H		420.5	**
16	2-Pyridyl	H		434.6	***
17	3-furyl	H	CH2CH2CH2N(Me)2	355.5	**
18	3-furyl	H		409.5	***
19	2-furyl	H		423.6	***
20	3-furyl	H		423.6	**
21	2-furyl	H		395.6	**
22	3-furyl	H		395.6	**
23	3-Pyridyl	H		434.6	**
24	2-Pyridyl	H		406.5	***
25	3-Pyridyl	H		406.6	**
26	3F-phenyl	H	CH2CH2CH2N(Me)2	383.5	***
27	3F-phenyl	H		437.6	**
28	3F-phenyl	H		451.6	***
29	2-pyrazinyl	H		407.3	**
30	2-pyrazinyl	H	CH2CH2CH2N(Me)2	367.3	***
31	2-benzofuranyl	H		445.3	**
32	2-benzofuranyl	H	CH2CH2CH2N(Me)2	405.3	**
33	2-benzofuranyl	H		459.4	**
34	2-benzofuranyl	H		473.4	**
35	5-isoxazolyl	H		424.3	*

Assay Protocols

The use of BIAcore biomolecular interaction analysis

[0090] Biotinylated human CD80 (hCD80-BT) is a recombinant soluble form of a membrane bound receptor molecule (CD80) which binds to CD28 to initiate T cell activation. The interaction between CD80 and CD28 has been extensively investigated (Collins et al, 2002). Biotinlyated human HLA-A2-tax is the recombinant soluble form of a membrane bound receptor molecule that has been used in this example as a control protein, and is not expected to interact with the compounds.

[0091] The BlAcore S51™ system was used for screening the compounds of Examples 1-4 above. A series S sensor chip CM5 was docked onto the BlAcore S51™. Streptavidin was coupled to the carboxymethyl surface using standard amine coupling. The chip surface was activated with 0.2M EDC / 0.05M NHS, followed by binding of streptavidin (0.25 mg/ml in 10 mM sodium acetate pH 5.0) and saturation of unoccupied sites with 1 M ethylenediamine.

[0092] The BlAcore S51 sensor chip has two separate sensor spots for immobilisation of proteins. hCD80-BT was immobilised on the streptavidin-coated surface of one sensor spot until a response of approximately 3000 RU was observed. A protein to control for non-specific binding of the compound was immobilised on a second sensor spot. The control protein used for these experiments was a biotinylated, soluble form of the human HLA protein.

[0093] Dilution series of compounds (1000nM - 0.05nM) were prepared in running buffer (10 mM, pH 7.4, 150 mM NaCl, 0.005% P20; 5% DMSO).

[0094] BlAcore S51™ was run at a flow rate of 30 µl/min using running buffer. Compounds and DMSO standard solutions for correction of data for solvent effects were injected. Data were recorded automatically and were analysed using BlAcore S51 Evaluation software.

[0095] The interaction between CD80 and the endogenous protein ligand (CD28) is highly specific, but relatively weak, with a K_D of 4750 nM, and an off-rate of greater than 0.2 s^-1 . The compounds of Examples 7, 11 & 18-21 have greater affinity and longer residence times on CD80 than CD28, having K_Ds of less than 100nM, and off-rates of 2x10^-2, indicating that the pyrazolones will be able to compete effectively with the endogenous ligand. The pyrazolones showed no detectable interaction with the control protein.

References

[0096] Collins AV et al. (2002) Immunity 17, 201-210 "The interaction properties of costimulatory molecules revisited"

Inhibition of production of interleukin-2 (IL-2) by human Jurkat T cells. Method

[0097] Human Raji cells were dispensed at a concentration of 2x10⁵ cells per well in RPMI-1640 medium supplemented with 10% fetal calf serum, 1% penicillin/streptomycin, 1% glutamine (RPMI medium) in a 96-well round bottom microtitre plate. Compounds under investigation (dissolved in 100% DMSO) were diluted to eight-fold the desired final concentration in RPMI medium and added to the required final concentration for a total volume of 200µl per well. After 20 minutes incubation at 37°C, Jurkat T cells were added at a concentration of 2x10⁵ cells per well. Monoclonal antibody to CD3 (UCHT1, R&D Systems) was added to the cultures at a final concentration of 1µg per ml, and where indicated, monoclonal antibody to CD28 (CD28.2, BD-Pharmingen) was also added at a concentration of 2.5µg per ml. Cells were cultured at 37°C for 5 hours, after which the plates were centrifuged and the supernatants harvested for IL-2 ELISA assay using the IL-2 Eli-pair kit (DIACLONE Research, Besancon, France) according to the manufacturers instructions.

[0098] By way of example, the compound of Example 26 gave 52% inhibition at 30 µM.

Homogenous Time Resolved Fluorescence Assay

[0099] The examples described above were tested in a cell free Homogenous Time Resolved Fluorescence (HTRF) assay to determine their activity as inhibitors of the CD80-CD28 interaction.

[0100] In the assay, europium and allophycocyanin (APC) are associated with CD28 and CD80 indirectly (through antibody linkers) to form a complex, which brings the europium and APC into close proximity to generate a signal. The complex comprises the following six proteins: fluorescent label 1, linker antibody 1, CD28 fusion protein, CD80 fusion protein, linker antibody 2, and fluorescent label 2. The table below describes these reagents in greater detail.

Fluorescent label 1	Anti-Rabbit IgG labelled with Europium (1µg/ml)
Linker antibody 1	Rabbit IgG specific for mouse Fc fragment (3µg/ml)
CD28 fusion protein	CD28 - mouse Fc fragment fusion protein (0.48µg/ml)
CD80 fusion protein	CD80 mouse Fab fragment (C215) fusion protein (1.9/µg/ml)
Linker antibody 2	GαMK-biotin: biotinylated goat IgG specific for mouse kappa chain (2µg/ml)
Fluorescent label 2	SA-APC: streptavidin labelled allophycocyanin (8µg/ml)

[0101] On formation of the complex, europium and APC are brought into proximity and a signal is generated.

[0102] Non-specific interaction was measured by substituting a mouse Fab fragment (C215) for the CD80 mouse Fab fragment fusion protein (1.9µg/ml). The assay was carried out in black 384 well plates in a final volume of 30µl. Assay buffer: 50mM Tris-HCl, 150mM NaCl pH7.8, containing 0.1 % BSA (w/v) added just prior to use.

[0103] Compounds were added to the above reagents in a concentration series ranging between 100µM - 1.7nM. The reaction was incubated for 4 hours at room temperature. Dual measurements were made using a Wallac Victor 1420 Multilabel Counter. First measurement: excitation 340nm, emission 665nm, delay 50µs, window time 200µs. second measurement: excitation 340nm, emission 615nm, delay 50µs, window time 200µs. Counts were automatically corrected for fluorescence crossover, quenching and background. The EC50 activities of compounds tested are recorded as: EC50: * = >10 µM, ** = 1-10 µM, *** = <1 µM.

Claims

1. A compound of formula (IC) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof:

wherein
Ar represents an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group having from 5 to 10 ring atoms,
R₆ represents a radical of formula -Alk-Q wherein
Alk is an optionally substituted divalent straight or branched C₁-C₁₂ alkylene, or C₂-C₁₂ alkenylene, or C₂-C₁₂ alkynylene radical or a divalent C₃-C₁₂ carbocyclic radical, any of which radicals may be interrupted by one or more -O-, -S- or -N(R₈)- radicals wherein R₈ represents H or C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, or C₃-C₆ cycloalkyl, and
Q represents -NR₈R₈ wherein each R₈ may be the same or different, or form a ring when taken together with the nitrogen to which they are attached; and
R₇ represents H or C₁-C₆ alkyl; or when taken together with the atom or atoms to which they are attached R₆ and R₇ form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms.

2. A compound as claimed in claim 1 wherein Alk is -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, or -CH₂CH(CH₃)CH₂-, or a divalent cyclopropylene, cyclopentylene or cyclohexylene radical, optionally substituted by OH, oxo, CF₃, methoxy or ethoxy, and Q represents -NR₈R₈ wherein each R₈ may be the same or different and selected from hydrogen, methyl, ethyl, n- or isopropyl or tert-butyl.

3. A compound as claimed in claim 1 or claim 2 wherein R₇ represents hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl; or when taken together with the atom or atoms to which they are attached R₆ and R₇ form a monocyclic heterocyclic ring having 5, 6 or 7 ring atoms.

4. A compound as claimed in any of the preceding claims wherein Ar is optionally substituted phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-furyl, 2-, or 3-thienyl, benzfur-2-yl, or benzthien-2-yl.

5. A compound as claimed in any of the preceding claims wherein Ar is substituted by F, Cl, methyl, methoxy, or methylenedioxy.

6. A compound as claimed in any of claims 1 to 4 wherein Ar is 3-fluorophenyl, or 2-or 3-furyl.

7. A pharmaceutical or veterinary composition comprising a compound as claimed in any of claims 1 to 6 together with a pharmaceutically or veterinarily acceptable excipient or carrier.

Ansprüche

1. Verbindung der Formel (IC) oder ein pharmazeutisch oder tierärztlich akzeptables Salz, Hydrat oder Solvat davon:

wobei
Ar eine gegebenenfalls substituierte monozyklische oder bizyklische aromatische oder heteroaromatische Gruppe mit 5 bis 10 Ringatomen repräsentiert,
R₆ einen Rest der Formel -Alk-Q repräsentiert, wobei
Alk ein gegebenenfalls substituierter zweibindiger geradkettiger oder verzweigter C₁-C₁₂-Alkylen- oder C₂-C₁₂-Alkenylen- oder C₂-C₁₂-Alkinylen-Rest ist oder ein zweibindiger C₃-C₁₂-carbozyklischer Rest, wobei jeder dieser Reste durch eine oder mehrere -O-, -S- oder -N(R₈)-Reste unterbrochen sein kann, wobei R₈ H oder C₁-C₄-Alkyl, C₃-C₄-Alkenyl, C₃-C₄-Alkinyl oder C₃-C₆-Cycloalkyl repräsentiert, und
Q -NR₈R₈ repräsentiert, wobei jedes R₈ dasselbe oder unterschiedlich sein kann, oder sie bilden einen Ring, wenn zusammengenommen mit dem Stickstoff, an welchen sie gebunden sind; und
R₇ H oder C₁-C₆-Alkyl repräsentiert; oder, wenn zusammen genommen mit dem Atom oder den Atomen, an welche sie gebunden sind, bilden R₆ und R₇ einen monozyklischen heterozyklischen Ring mit 5, 6 oder 7 Ringatomen.

2. Verbindung nach Anspruch 1, wobei Alk -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂- oder -CH₂CH(CH₃)CH₂- oder ein zweibindiger Cyclopropylen-, Cyclopentylen- oder Cyclohexylen-Rest ist, gegebenenfalls substituiert mit OH, Oxo, CF₃, Methoxy oder Ethoxy, und Q repräsentiert -NR₈R₈, wobei jedes R₈ dasselbe oder unterschiedlich sein kann und ausgewählt sein kann aus Wasserstoff, Methyl, Ethyl, n- oder iso-Propyl oder tert-Butyl.

3. Verbindung nach Anspruch 1 oder 2, wobei R₇ Wasserstoff, Methyl, Ethyl, n- oder iso-Propyl, n-, sec- oder tert-Butyl repräsentiert; oder wenn zusammen genommen mit dem Atom oder den Atomen, an welche sie gebunden sind, bilden R₆ und R₇ einen monozyklischen heterozyklischen Ring mit 5, 6 oder 7 Ringatomen.

4. Verbindung nach einem beliebigen der vorhergehenden Ansprüche, wobei Ar gegebenenfalls mit Phenyl, 2-, 3- oder 4-Pyridyl, 2- oder 3-Furyl, 2- oder 3-Thienyl, Benzfur-2-yl oder Benzthien-2-yl substituiert ist.

5. Verbindung nach einem beliebigen der vorhergehenden Ansprüche, wobei Ar mit F, Cl, Methyl, Methoxy oder Methylendioxy substituiert ist.

6. Verbindung nach einem beliebigen der Ansprüche 1 bis 4, wobei Ar 3-Fluorphenyl oder 2- oder 3-Furyl ist.

7. Pharmazeutische oder tierärztliche Zusammensetzung, umfassend eine Verbindung nach einem beliebigen der Ansprüche 1 bis 6 zusammen mit einem pharmazeutisch oder tierärztlich akzeptablen Hilfsstoff oder Träger.

Revendications

1. Composé de formule (IC) ou un de ses sels, hydrates ou solvates acceptables pour une utilisation vétérinaire ou pharmaceutique

dans laquelle
Ar représente un groupe monocyclique ou bicyclique, aromatique ou hétéroaromatique, optionnellement substitué, ayant 5 à 10 atomes de cycle,
R₆ représente un radical de formule -Alk-Q dans lequel
Alk est un radical C₁-C₁₂ alkylène, C₂-C₁₂ alcénylène, ou C₂-C₁₂ alcynylène divalent, linéaire ou ramifié, optionnellement substitué, ou un radical C₃-C₁₂ carbocyclique divalent, chacun de ces radicaux pouvant être interrompus par un ou plusieurs radicaux -O-, -S- ou -N(R₈) où R₈ représente H ou un C₁-C₄ alkyle, un C₃-C₄ alcényle, un C₃-C₄ alcynyle, ou un C₃-C₆ cycloalkyle, et
Q représente -NR_SR_B où chaque R₈ peut être identique ou différent, ou pris ensemble, les deux R₈ forment un cycle avec l'azote auquel ils sont liés ; et
R₇ représente H ou un C₁-C₆ alkyle, ou R₆ et R₇ pris ensemble avec le ou les atomes auxquels ils sont liés, forment un cycle monocyclique hétérocyclique ayant 5, 6 ou 7 atomes de cycle.

2. Composé selon la revendication 1 dans lequel Alk est -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, ou -CH₂CH(CH₃)CH₂-, ou un radical cyclopropylène divalent, un radical cyclopentylène ou un radical cyclohexylène, éventuellement substitué par OH, oxo, CF₃, méthoxy ou éthoxy, et Q représente -NR₈R₈- dans lequel chaque R₈ peut être identique ou différent et choisi parmi l'hydrogène, le méthyle, l'éthyle, le n- ou iso-propyle ou le tert-butyle.

3. Composé selon l'une quelconque des revendications 1 et 2 dans lequel R₇ représente l'hydrogène, le méthyle, l'éthyle, le n- ou iso-propyle, le n-, sec-, ou tert-butyle ; ou R₆ et R₇, pris ensemble avec le ou les atomes auxquels ils sont liés, forment un cycle monocyclique ou hétérocyclique ayant 5, 6 ou 7 cycles d'atomes.

4. Composé selon l'une quelconque des revendications précédentes, dans lequel Ar est optionnellement substitué par le phényle, le 2- ou le 3- ou le 4-pyridyle, le 2- ou le 3-furyle, le 2- ou le 3-thiényle, le benzfur-2-yle, ou le benzthièn-2-yle.

5. Composé selon l'une quelconque des revendications précédentes, dans lequel Ar est substitué par F, CI, méthyle, méthoxy, ou méthylènedioxy.

6. Composé selon l'une quelconque des revendications 1 à 4 dans lequel Ar est le 3-fluorophényle, ou le 2- ou le 3-furyle.

7. Composition pharmaceutique ou vétérinaire comprenant un composé selon l'une quelconque des revendications 1 à 6 associé à un excipient ou un véhicule acceptable pour une utilisation pharmaceutique ou vétérinaire.